von Willebrand Disease

vWD is the most common inherited bleeding disorder.

vWF serves two roles:

(1) as the major adhesion molecule that tethers the platelet to the exposed subendothelium

(2) as the binding protein for FVIII, resulting in significant prolongation of the FVIII half-life in circulation.

 The platelet-adhesive function of vWF is critically dependent on the presence of large vWF multimers, while FVIII binding is not. Most of the symptoms of vWD are "platelet-like" except in more severe vWD when the FVIII is low enough to produce symptoms similar to those found in Factor VIII deficiency (hemophilia A).

vWD has been classified into three major types, with four subtypes of type 2. By far the most common type of vWD is type 1 disease, with a parallel decrease in vWF protein, vWF function, and FVIII levels, accounting for at least 80% of cases. Patients have predominantly mucosal bleeding symptoms, although postoperative bleeding can also be seen. Bleeding symptoms are very uncommon in infancy and usually manifest later in childhood with excessive bruising and epistaxis. Since these symptoms occur commonly in childhood, the clinician should particularly note bruising at sites unlikely to be traumatized and/or prolonged epistaxis requiring medical attention. Menorrhagia is a common manifestation of vWD. Menstrual bleeding resulting in anemia should warrant an evaluation for vWD and, if negative, functional platelet disorders. Frequently, mild type 1 vWD first manifests with dental extractions, particularly wisdom tooth extraction, or tonsillectomy.



Not all patients with low vWF levels have bleeding symptoms. Whether patients bleed or not will depend on the overall hemostatic balance they have inherited, along with environmental influences and the type of hemostatic challenges they experience. Although the inheritance of vWD is autosomal, many factors influence both vWF levels and bleeding symptoms. These have not all been defined but include blood type, thyroid hormone status, race, stress, exercise, and hormonal (both endogenous and exogenous) influences. Patients with type O blood have vWF protein levels about one-half those of patients with AB blood type; in fact, the normal range for patients with type O blood overlaps that usually considered diagnostic for vWD. A mildly decreased vWF level should perhaps be viewed more as a risk factor for bleeding than as an actual disease.

Patients with type 2 vWD have functional defects; thus, the vWF antigen measurement is significantly higher than the test of function. For types 2A, 2B, and 2M, vWF activity is decreased, measured as ristocetin cofactor or collagen binding activity. In type 2A vWD, the impaired function is due either to increased susceptibility to cleavage by ADAMTS13, resulting in loss of intermediate- and high-molecular weight (M.W.) multimers, or to decreased secretion of these multimers by the cell. Type 2B vWD results from gain of function mutations that result in increased spontaneous binding of vWF to platelets in circulation, with subsequent clearance of this complex by the reticuloendothelial system. The resulting vWF in the patients' plasma lacks the highest M.W. multimers, and the platelet count is usually modestly reduced. Type 2M results from a group of mutations that cause dysfunction of the molecule but do not affect multimer structure.

Type 2N vWD reflects mutations in vWF that preclude binding of FVIII. As FVIII is stabilized by binding to vWF, the FVIII in patients with type 2N vWD has a very short half-life, and the FVIII level is markedly decreased. This is sometimes termed autosomal hemophilia. Type 3 vWD, or severe vWD, describes patients with virtually no vWF antigen (usually <10%). Patients experience mucosal and joint postoperative symptoms as well as other bleeding symptoms. Some patients with type 3 vWD, particularly those with large vWF gene deletions, are at risk of developing antibodies to infused vWF.

Acquired vWD is a rare disorder, most commonly seen in patients with underlying lymphoproliferative disorders, including monoclonal gammopathies of undetermined significance (MGUS), multiple myeloma, and Waldenstrom's macroglobulinemia. It is seen most commonly in the setting of MGUS and should be suspected in patients, particularly elderly patients, with a new onset of severe mucosal bleeding symptoms.

Heyde's syndrome (aortic stenosis with gastrointestinal bleeding) is attributed to the presence of angiodysplasia of the gastrointestinal tract in patients with aortic stenosis. However, the shear stress on blood passing through the stenotic aortic valve appears to produce a change in vWF, making it susceptible to serum proteases. Consequently, large multimer forms are lost, leading to an acquired type 2 vWD, but return when the stenotic valve is replaced.

von Willebrand Disease: Treatment

The mainstay of treatment for type 1 vWD is 1-deamino-8-D-arginine vasopressin (DDAVP, or desmopressin), which results in release of vWF and FVIII from endothelial stores. DDAVP can be given intravenously or by an intranasal spray (1.5 mg/mL). The peak activity when given intravenously is approximately 30 min, while it is 2 h when given intranasally. The usual dose is 0.3 g/kg intravenously or 2 squirts (1 in each nostril) for patients >50 kg (1 squirt for those <50 kg). It is recommended that patients with vWD be tested with DDAVP to assess their response before using it.

In patients who respond well (increase in values of two- to fourfold), it can be used for procedures with minor-to-moderate risk of bleeding. Depending on the procedure, additional doses may be needed; it is usually given every 12–24 h. Less frequent dosing may result in less tachyphylaxis, which occurs when synthesis cannot compensate for the released stores. The major side effect of DDAVP is hyponatremia due to decreased free water clearance. This occurs most commonly in the very young and the very old, but fluid restriction should be advised for all patients for the 24 hours following each dose.

Some patients with types 2A and 2M vWD respond to DDAVP such that it can be used for minor procedures. For the other subtypes, for type 3 disease, and for major procedures requiring longer periods of normal hemostasis, vWF replacement can be given. Virally inactivated vWF-containing factor concentrates are thought to be safer than cryoprecipitate as the replacement product. Humate-P is the only FDA-approved product for this indication in the United States. Other concentrates have been studied in vWD, and a vWF concentrate is available in some countries in Europe.

Antifibrinolytic therapy, using either epsilon-aminocaproic acid or tranexamic acid, is an important therapy, either alone or in an adjunctive capacity, particularly for the prevention or treatment of mucosal bleeding. These agents are particularly useful in prophylaxis for dental procedures, with DDAVP for dental extractions and tonsillectomy, menorrhagia, and prostate procedures. It is contraindicated in the setting of upper urinary tract bleeding, due to the risk of ureteral obstruction.